This invention relates generally to a method for attenuating free radical formation resulting from a bodily insult, and more specifically, to a method for protecting solid organs against injury caused by disruption of a chemical environment in the solid organ and to a method for protecting tissue from injury related to an exposure of a injurious agent to that solid organ tissue. The method protects the solid organ and tissues within that solid organ by administering a prophylactic solution into the body to alter the acid-base balance. In one particular application, the invention is a method applied when administering a radiographic contrast medium in a manner which reduces the incidence of contrast-induced nephropathy (CIN). In another particular application, the invention is a method applied when administering a radiographic contrast medium in a manner which reduces the cardiac injury (resulting in death) associated with the contrast media injection in cardiac arteries.
The kidneys' main function is to eliminate excess fluid and waste material from the blood. When the kidneys lose this filtering ability, dangerous levels of fluid and waste accumulate in the body causing kidney (renal) failure. Acute kidney failure is most likely to happen after complicated surgery or severe injuries, or when blood vessels leading to the kidneys become blocked or experience low blood pressure, or when the kidneys are exposed to chemical compounds that are potentially toxic. Conversely, chronic kidney failure usually develops slowly with few symptoms in the early stages. Many people with chronic kidney failure have no symptoms until their kidney function has decreased to less than 25 percent of normal. High blood pressure and diabetes are the most common causes of chronic kidney failure.
One adult kidney contains roughly a million nephrons, each consisting of a tuft of capillary blood vessels (glomerulus) and tubules that lead to the collecting system and, eventually, to the bladder. Each tuft of capillaries filters fluid from the bloodstream, and passes the filtrate to a tubule. The filtrate contains both waste products and substances vital for health. From the tubules, waste byproducts such as urea, uric acid and creatinine are excreted in urine while substances the body needs such as glucose, proteins, amino acids, calcium and salts are absorbed by the tubules back into the bloodstream. While this unique filtration system is generally able to clear all the waste products produced by the body, problems can occur if the fragile tubules or glomeruli are damaged or diseased.
Many conditions and circumstances can damage kidneys, including intrinsic kidney disease or injury, high blood pressure, diabetes mellitus, exposure to toxins and certain medications, kidney stones, tumors and even infections in other parts of your body. Many conditions and circumstances can damage tissue, including exposure to toxins and certain medications that can stimulate free radical formation, often accentuated in the ischemic tissue and in tissue where the acid-base balance is in favor of the acid. Many of these conditions for the kidney or the other tissue areas may show no signs or symptoms until irreparable damage has occurred.
The mechanism of the vast majority of acute kidney damage and tissue injury is often modulated by the formation of free radicals known to be increased in an acid environmental (pH that is low compared to normal body pH). One of the functions of the kidney is to regulate acid-base metabolism by actively absorbing the filtered bicarbonate and generating bicarbonate, while excreting the typical acid load of subjects. This process of eliminating the “acid load” causes the generation of renal tubular fluid which is relatively acidic compared to normal tissue. This acid environment could accelerate the formation of free radicals under certain conditions. Other potentially injured tissue may have reduced blood delivery or high concentrations of toxic chemicals or drug and thus potentially have inadequate base to buffer the free radicals formed by toxic condition or toxic chemical or drug. Existing medical references support the attenuation of free radical formation by inducing a more normal pH environment in the kidney and in tissue that has overwhelming exposure to toxic conditions or toxic chemicals or drugs.
The use of iodinated, radiographic contrast (RC) media has long been recognized as a contributing factor in acute kidney dysfunction. Examples of imaging and medical procedures requiring the use of RC include Computerized Tomographic (“CT”) scan enhancement, arteriograms, cardiac catherization, vascular studies, stents, lumbar myelography, thoraco-cervical myelography, cerebral angiography, peripheral arteriography, venography, angiocardiography, left ventriculography, selective visceral arteriography, digital subtraction abgiography, urography, arthrography, and computer tomography angiography (“CTA”). The degree of acute kidney dysfunction—labeled “contrast induced nephropathy” (CIN)—ranges from a short-term slight increase in serum creatinine levels to overt kidney failure requiring temporary or permanent dialysis, and in some cases resulting in death. CIN is broadly defined as a rise in serum creatinine levels in relation to the administration of contrast media. CIN has been reported to be the third most common cause of kidney insufficiency occurring in hospitalized patients, and it might be a factor in up to 10 percent of all cases of acute kidney failure.
Iodinated contrast in high concentration will have a similar effect on other solid organ tissues, thus the formation of free radicals can further the injury the tissue of these solid organs, in particular the heart when the iodinated contrast is injected directly in the cardiac vessels. The heart tissue behind heart artery obstruction(s) or heart tissue with inadequate blood flow from any cause is likely to become “ischemic” when the work of the heart is increased or when contrast medium is injected into these areas. An abnormal or low blood flow may alter the acid-balance in this “ischemic” tissue thus leading to an increase in free radical formation leading to further tissue damage. This condition is mediated by the method described in this patent. Increased bicarbonate can alter the acid-balance in these “ischemic” areas to reduce or eliminate the free radical formation and subsequent damage.
Prior art efforts to treat kidney dysfunction recognize the use of a sodium bicarbonate infusion. These existing methods, however, are fraught with complications, drawbacks, and inconclusive test results.
Complications of Bicarbonate Infusions
Hypertonic solutions of sodium bicarbonate (8.4% or 1 Molar) are supplied in most hospitals in 50 mL ampules to be administered slowly, or added to other intravenous solutions. Rapid infusions or excessive volumes of this hypertonic solution are known to cause serious injury. This injury can occur in the form of a rapid depression of serum potassium and subsequent cardiac rhythm disturbances (even fatal disturbances), depression of serum ionized calcium with an associated drop in blood pressure, hemolysis or breakdown of red cells as a result of the high osmolar solution, and severe pain and tissue necrosis at the site of an intravenous extravagation.
If sodium bicarbonate is prepared in a solution with a concentration of 25 to 50 mEq/L, as directed in prior U.S. Pat. No. 5,112,622, then the volume required to reach a target level of 2 mEq/kg (of subject weight) in a 70 kg subject would be 5.6 liters to 2.8 liters. This volume is large and a challenge for normal subjects to tolerate in an eight hour period, and entirely unacceptable and dangerous as an administered dose of fluids to “sick” or elderly subjects undergoing a substantial medical procedure, such as cardiac catheterization or cardiac surgery. The critical care literature is full of references to the danger of sodium bicarbonate infusions in critically ill subjects.
The bicarbonate pretreatment of the present invention has been shown to nearly eliminate acute kidney failure associated with contrast exposure. Similar evidence shows that similar doses can reduce cardiac associated death with exposure to iodinated contrast. The choice of bicarbonate concentration in the 100 to 300 mEq/L range allows an effective dose of solution to be administered in a volume of fluid that is well tolerated by “sick” subjects undergoing the diagnostic or therapeutic procedure.
Since many other causes of kidney dysfunction (other than CIN and ischemia from low blood pressure) are induced by the free radical formation process, the present method can also be expected to respond favorably against these disruptions by similar administration of bicarbonate, provided excessive volume and excessive concentration can be avoided. Suggested prior art treatments using sodium bicarbonate, such as described in the '622 Patent, would require a volume of fluid in excess of what even a normal subject could be expected to tolerate without death or serious complications. The present invention may identify an effective and tolerable dose of the bicarbonate anion, concentration of the anion, and timely administration necessary for a successful prophylaxis.
The terms “organ” and “organ tissue” are broadly defined herein to mean the solid human organ that is distal to and perfused by the artery which receives the administration (e.g., injection) of contrast media. The “organ tissue” is that human tissue distal to the site of arterial injection of the iodinated contrast agent, and refers specifically to the tissue perfused beyond the injection site which could represent a portion of a human solid organ (heart or brain) or one leg or a portion of one leg, depending on the injection site of the contrast media.